Adult Faconi Syndrome Secondary to Light Chain Gammopathy: Clinicopathologic Heterogeneity and Unnsual Features in 11 Patients

Abstract

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation

“…12 Additionally, some patients with a plasma cell dyscrasia and clear evidence of proximal tubule injury leading to Fanconi syndrome show neither crystal formation in the proximal tubules nor casts in the distal tubules. 4 These studies strongly suggest that the presence of excess free-light chains is sufficient to cause injury to renal proximal tubular cells whether or not crystals develop in the proximal tubular cytoplasm.…”

“…[4][5][6][7][8]15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] In these cases, 53/56 showed the presence of intracytoplasmic crystals in the proximal tubular cells and 37/40 proved to be of the k subtype. The three previous cases without crystal formation were all reported by Kapur et al 5 in one paper.…”

“…These patients frequently present with Fanconi syndrome in the setting of smoldering myeloma. 4 Occasionally, cases are seen with light chain restriction in the proximal tubules that have no evidence of crystal formation in the proximal tubular cytoplasm. These cases of light chain proximal tubulopathy without crystal deposition are only loosely related to the typical light chain proximal tubulopathy.…”

A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine

“…Other glomerular entities include MIDD, which is comprised of the variants light-chain deposition disease (LCDD), heavy-chain deposition disease, and light-and heavy-chain deposition disease named for the types of Ig deposits found in the kidney, and proliferative glomerulonephritidies, such as membranoproliferative GN and PGNMID (5,11). In the tubules, light-chain proximal tubulopathy (LCPT) with or without Fanconi syndrome and cast nephropathy are conditions associated with MG (18). Rare cases of diabetes insipidus have been reported with AL amyloidosis that have deposited in the distal tubules (19).…”

“…There are two exceptions. One is light-chain Fanconi syndrome, where the presence of amino aciduria, normoglycemic glycosuria, hypophosphatemia, hypouricemia, and hypokalemia along with renal impairment and subnephrotic-range proteinuria are diagnostic (18). The other is AL amyloidosis, where the diagnosis can be established by nephrotic-range proteinuria and amyloid found in nonrenal tissue (54).…”